The candidate's long-term career goal as a physician-scientist is to conduct investigator-initiated research into the molecular basis of the human immune response to viruses. Immediate goals include acquisition of skills in molecular virology and immunology studies in animals. These skills are critical to complement the candidate's extensive training in molecular human immunology acquired during previous studies of the human antibody response to respiratory syncytial virus (RSV). The experience gained during this project will prepare the candidate broadly to conduct unique studies of the immunobiology of early childhood pathogens. Human metapneumovirus (hMPV) is a newly described paramyxovirus that infects most humans by the age of five years. Our preliminary data indicate that hMPV is a major cause of lower respiratory tract infection (LRI) in children with a spectrum of illness and morbidity similar to that of RSV. This work proposes to define the antigenic determinants of protective immunity to hMPV, providing foundational new knowledge about the host immune response to this important emerging pathogen. The central hypothesis of this proposal is that the hMPV surface glycoproteins F (fusion) and G (attachment) are the major determinants of protective immunity and that protection is mediated by humoral antibody. Specific aim #1 is to investigate the antibody response to hMPV F and G proteins expressed in a novel vaccinia-virus based mammalian system. These recombinant antigens will be critical tools to evaluate the host immune response to hMPV. Specific aim #2 is to determine whether hMPV F and G surface proteins expressed by recombinant vaccinia virus are major protective antigens in a rodent model. These experiments will identify the determinants of protective immunity and define antigenic diversity between hMPV strains. Specific aim # 3 is to determine if humoral antibody alone is sufficient to mediate protection against recurrent LRI caused by hMPV. This work will provide valuable new data regarding the host immune response to an important respiratory pathogen of childhood that will be applicable to studies of human immunopathology associated with hMPV infection. The elucidation of the mechanism of protective immunity will also be important for future development of potential vaccines. The proposed work will provide the candidate skills and experience to be an outstanding physician-scientist in the field of human viral immunology.